N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy

Dystroglycan (DG) requires extensive post-translational processing and O-glycosylation to function as a receptor for extracellular matrix (ECM) proteins containing laminin-G (LG) domains. Matriglycan is an elongated polysaccharide of alternating xylose (Xyl) and glucuronic acid (GlcA) that binds with high affinity to ECM proteins with LG domains and is uniquely synthesized on alpha-dystroglycan (alpha-DG) by like-acetylglucosaminyltransferase-1 (LARGE1). Defects in the post-translational processing or O-glycosylation of alpha-DG that result in a shorter form of matriglycan reduce the size of alpha-DG and decrease laminin binding, leading to various forms of muscular dystrophy. Previously, we demonstrated that protein O-mannose kinase (POMK) is required for LARGE1 to generate full-length matriglycan on alpha-DG (similar to 150-250 kDa) (Walimbe et al., 2020). Here, we show that LARGE1 can only synthesize a short, non-elongated form of matriglycan in mouse skeletal muscle that lacks the DG N-terminus (alpha-DGN), resulting in an similar to 100-125 kDa alpha-DG. This smaller form of alpha-DG binds laminin and maintains specific force but does not prevent muscle pathophysiology, including reduced force production after eccentric contractions (ECs) or abnormalities in the neuromuscular junctions. Collectively, our study demonstrates that alpha-DGN, like POMK, is required for LARGE1 to extend matriglycan to its full mature length on alpha-DG and thus prevent muscle pathophysiology.

Automated summary

Post-translational processing and O-glycosylation are critical for the function of Dystroglycan (DG) as a receptor for extracellular matrix (ECM) proteins. Our study demonstrates the importance of protein O-mannose kinase (POMK) and alpha-DGN in the synthesis of matriglycan by LARGE1.